Ocular transfer of retinal glial cells transduced ex vivo with adenovirus expressing viral IL-10 or CTLA4-Ig inhibits experimental autoimmune uveoretinitis

Verwaerde, Claudie; Naud, Marie‐Christine; Delanoye, Anne; Wood, Matthew; Thillaye-Goldenberg, B.; Auriault, Claude; Kozak, Y. de

doi:10.1038/sj.gt.3302101

Cited by 36 publications

(16 citation statements)

References 52 publications

(61 reference statements)

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“…De Kozak et al applied ocular gene therapy with live cells or an adeno-associated virus construct engineered to express IL-10 (29,30). Such forced local expression of IL-10 protects mice from EAU and is likely to represent local inhibitory effects on effector cells entering the ocular environment.…”

Section: Discussionmentioning

confidence: 99%

Abrogation of Anti-Retinal Autoimmunity in IL-10 Transgenic Mice Due to Reduced T Cell Priming and Inhibition of Disease Effector Mechanisms

Agarwal

Horai

Viley

et al. 2008

The Journal of Immunology

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Experimental autoimmune uveitis (EAU) induced by immunization of animals with retinal Ags is a model for human uveitis. The immunosuppressive cytokine IL-10 regulates EAU susceptibility and may be a factor in genetic resistance to EAU. To further elucidate the regulatory role of endogenous IL-10 in the mouse model of EAU, we examined transgenic (Tg) mice expressing IL-10 either in activated T cells (inducible) or in macrophages (constitutive). These IL-10-Tg mice and non-Tg wild-type controls were immunized with a uveitogenic regimen of the retinal Ag interphotoreceptor retinoid-binding protein. Constitutive expression of IL-10 in macrophages abrogated disease and reduced Ag-specific immunological responses. These mice had detectable levels of IL-10 in sera and in ocular extracts. In contrast, expression of IL-10 in activated T cells only partially protected from EAU and marginally reduced Ag-specific responses. All IL-10-Tg lines showed suppression of Ag-specific effector cytokines. APC from Tg mice constitutively expressing IL-10 in macrophages exhibited decreased ability to prime naive T cells, however, Ag presentation to already primed T cells was not compromised. Importantly, IL-10-Tg mice that received interphotoreceptor retinoid-binding protein-specific uveitogenic T cells from wild-type donors were protected from EAU. We suggest that constitutively produced endogenous IL-10 ameliorates the development of EAU by suppressing de novo priming of Ag-specific T cells and inhibiting the recruitment and/or function of inflammatory leukocytes, rather than by inhibiting local Ag presentation within the eye.

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Section: Discussionmentioning

confidence: 99%

Abrogation of Anti-Retinal Autoimmunity in IL-10 Transgenic Mice Due to Reduced T Cell Priming and Inhibition of Disease Effector Mechanisms

Agarwal

Horai

Viley

et al. 2008

The Journal of Immunology

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“…The brief duration of intraocular transgene expression following injection of the recombinant adenoviral vector can be prolonged by intravitreal transfer of syngeneic retinal Muller glial cells that have been transfected by the same vector ex vivo. 47 rAAV-2-mediated expression of IL-10 significantly decreases disease severity of EAU without affecting splenocyte proliferative responses or serum antibody levels, illustrating the potential of gene therapy strategies to modulate immune responses in local microenvironments without unwanted systemic effects. 48 Expression of CNTF or GDNF by adenoviral and lentiviral vectors prolong retinal ganglion cell survival following axonal injury.…”

Section: Intraocular Gene Transfer Of Therapeutic Proteins Can Modifymentioning

confidence: 99%

Gene therapy progress and prospects: the eye

2006

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“…In EAU, ICOS expression has been reported to be upregulated, and attenuation of ICOS function has been shown to reduce the disease severity (39,40). The therapeutic potential of CTLA4-Ig in EAU was also demonstrated (41). Nevertheless, no studies have been reported, to the best of our knowledge, that examine whether HVEM cosignaling has any pathogenic functions in EAU and, if any, whether regulation of these functions can be beneficial in the treatment of EAU.…”

Section: Discussionmentioning

confidence: 83%

Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses

Sakoda

Nagai

Murata

et al. 2016

The Journal of Immunology

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Herpesvirus entry mediator (HVEM), a member of the TNFR superfamily, serves as a unique molecular switch to mediate both stimulatory and inhibitory cosignals, depending on its functions as a receptor or ligand interacting with multiple binding partners. In this study, we explored the cosignaling functions of HVEM in experimental autoimmune uveitis (EAU), a mouse model resembling human autoimmune uveitis conditions such as ocular sarcoidosis and Behcet disease. Our studies revealed that EAU severity significantly decreased in HVEM-knockout mice compared with wild-type mice, suggesting that stimulatory cosignals from the HVEM receptor are predominant in EAU. Further studies elucidated that the HVEM cosignal plays an important role in the induction of both Th1- and Th17-type pathogenic T cells in EAU, including differentiation of IL-17–producing αβ+γδ− conventional CD4+ T cells. Mice lacking lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT), B- and T-lymphocyte attenuator (BTLA) or both LIGHT and BTLA are also less susceptible to EAU, indicating that LIGHT–HVEM and BTLA–HVEM interactions, two major molecular pathways mediating HVEM functions, are both important in determining EAU pathogenesis. Finally, blocking HVEM cosignals by antagonistic anti-HVEM Abs ameliorated EAU. Taken together, our studies revealed a novel function of the HVEM cosignaling molecule and its ligands in EAU pathogenesis through the induction of Th1- and Th17-type T cell responses and suggested that HVEM-related molecular pathways can be therapeutic targets in autoimmune uveitis.

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Ocular transfer of retinal glial cells transduced ex vivo with adenovirus expressing viral IL-10 or CTLA4-Ig inhibits experimental autoimmune uveoretinitis

Cited by 36 publications

References 52 publications

Abrogation of Anti-Retinal Autoimmunity in IL-10 Transgenic Mice Due to Reduced T Cell Priming and Inhibition of Disease Effector Mechanisms

Abrogation of Anti-Retinal Autoimmunity in IL-10 Transgenic Mice Due to Reduced T Cell Priming and Inhibition of Disease Effector Mechanisms

Gene therapy progress and prospects: the eye

Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses

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